Biology:PNKD

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

PNKD is the abbreviation for a human neurological movement disorder paroxysmal nonkinesiogenic dyskinesia. Like many other human genetics disorders, PNKD also refers to the disease, the disease gene and the encoded protein. (PNKD) is a protein that in humans is encoded by the PNKD gene.[1][2] Alternative splicing results in the transcription of three isoforms. The mouse ortholog is called brain protein 17 (Brp17).

Structure

This gene is located on chromosome 2 at the band 2q35 and contains 12 exons.[2] At least three isoforms of varying lengths (long, medium, and short) can be produced by alternative splicing of this gene. While the gene products of the long (PNKD-L) and medium (PNKD-M) isoforms contain the C-terminal β-lactamase domain, the short (PNKD-S) isoform, commonly referred to as myofibrillogenesis regulator-1 (MR-1), contains only three exons and lacks homology to any known protein.[3][4] These isoforms also differ in their tissue-specific expression and subcellular localization. Specifically, PNKD-L is only expressed in the central nervous system whereas PNKD-M and PNKD-S are ubiquitously expressed across tissues.[3] Moreover, PNKD-L localizes to the cell membrane, PNKD-S to the cytoplasm and nucleus, and PNKD-M to the mitochondrion.[5]

Function

The function of PNKD proteins are unknown but the long and medium isoforms of PNKD contain a conserved β-lactamase domain which suggest it may function as an enzyme. The closest mammalian homolog to PNKD is HAGH, an enzyme involves in a two-step reaction to hydrolyze SLG and produce D-lactic acid and reduced GSH. However, the hydrolytic activity of PNKD is minimal.[3]

The long form of PNKD is neuronal specific and encodes a synaptic protein that localizes dominantly to the pre-synaptic membrane. Post-synaptic area and vesicular structure also occasionally has PNKD long form. PNKD long form interacts with pre-synaptic protein RIM and inhibits synaptic exocytosis. PNKD with disease mutations is less effective in inhibition thus the synaptic release is increased. This would cause excessive neurotransmitter release in the brain and maybe the root cause for triggering epilepsy in PNKD patients.[6]

Clinical significance

Point mutations in PNKD exon 1 cause an inherited neurological movement disorder in humans called paroxysmal nonkinesigenic dyskinesia.[2] Overexpression of PNKD has also been associated with multiple cancers, including pancreatic ductal adenocarcinoma,[7] gastric cancer,[8] ovarian cancer,[9] and breast cancer[4] and may serve as a therapeutic target for treating these cancers or a biomarker for assessing patient outcomes. The signaling pathways involved may vary depending on the cancer. For instance, in human breast cancer (MCF7) cells, PNKD may promote tumor cell proliferation by activating the MEK/ERK signaling pathway, while in human hepatoma (HepG2) cells, PNKD may operate through the MLC2/FAK/AKT pathway.[4]

Interactions

PNKD has been shown to interact with:

  • Rab3-interacting molecule (RIM)1[6]
  • RIM2[6]

References

  1. ↑ "Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q". American Journal of Human Genetics 59 (1): 140–5. July 1996. PMID 8659518. 
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: PNKD paroxysmal nonkinesiogenic dyskinesia". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=25953. 
  3. ↑ 3.0 3.1 3.2 "Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability". Human Molecular Genetics 20 (12): 2322–32. June 2011. doi:10.1093/hmg/ddr125. PMID 21487022. 
  4. ↑ 4.0 4.1 4.2 "Phosphorylation of myofibrillogenesis regulator-1 activates the MAPK signaling pathway and induces proliferation and migration in human breast cancer MCF7 cells". FEBS Letters 588 (17): 2903–10. August 2014. doi:10.1016/j.febslet.2014.07.018. PMID 25066297. 
  5. ↑ "PNKD - Probable hydrolase PNKD - Homo sapiens (Human) - PNKD gene & protein". https://www.uniprot.org/uniprot/Q8N490. 
  6. ↑ 6.0 6.1 6.2 "Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis". Proceedings of the National Academy of Sciences of the United States of America 112 (10): 2935–41. March 2015. doi:10.1073/pnas.1501364112. PMID 25730884. Bibcode: 2015PNAS..112.2935S. 
  7. ↑ "Clinicopathological and prognostic significance of myofibrillogenesis regulator-1 protein expression in pancreatic ductal adenocarcinoma". Tumour Biology 34 (5): 2983–7. October 2013. doi:10.1007/s13277-013-0862-4. PMID 23696030. 
  8. ↑ "Myofibrillogenesis regulator-1 overexpression is associated with poor prognosis of gastric cancer patients". World Journal of Gastroenterology 18 (38): 5434–41. October 2012. doi:10.3748/wjg.v18.i38.5434. PMID 23082061. 
  9. ↑ "[Expression of a novel biomarker, MR-1S, in ovarian carcinoma and its biological significance]". Zhonghua Zhong Liu Za Zhi [Chinese Journal of Oncology] 34 (3): 176–81. March 2012. doi:10.3760/cma.j.issn.0253-3766.2012.03.004. PMID 22780969. 




Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:PNKD&oldid=3544632"